Synthetic studies toward the brasilinolides: controlled assembly of a protected C1-C38 polyol based on fragment union by complex aldol reactions.

The brasilinolides are an architecturally complex family of 32-membered macrolides, characterised by potent immunosuppressant and antifungal properties, which represent challenging synthetic targets. By adopting a highly convergent strategy, a range of asymmetric aldol/reduction sequences and catalytic protocols were employed to assemble a series of increasingly elaborate fragments. The controlled preparation of suitable C1-C19 and C20-C38 acyclic fragments 5 and 6, containing seven and 12 stereocentres respectively, was first achieved. An adventurous C19-C20 fragment union was then explored to construct the entire carbon chain of the brasilinolides. This pivotal coupling step could be performed in a complex boron-mediated aldol reaction to install the required C19 hydroxyl stereocentre when alternative Mukaiyama-type aldol protocols proved unrewarding. A protected C1-C38 polyol 93 was subsequently prepared, setting the stage for future late-stage diversification toward the various brasilinolide congeners. Throughout this work, asymmetric boron-mediated aldol reactions of chiral ketones with aldehydes proved effective both for controlled fragment assembly and coupling with predictable stereoinduction from the enolate component.We thank the EPSRC (EP/F025734/1) and Syngenta for support, the Isaac Newton–Mays Wild Research Fellowship at Downing College (M.P.H.), the Herchel Smith Postdoctoral Fellowships Fund at Cambridge (C.J.C.) and the Deutsche Akademie der Naturforser Leopoldina (F.A.M.; BMBF-LPD 9901/8-148) for additional funding, and the EPSRC National Mass Spectrometry Centre (Swansea) for mass spectra.This is the final published version of the article. It was originally published in Organic & Biomolecular Chemistry (Paterson I, Housden MP, Cordier CJ, Burton PM, Mühlthau FA, Loiseleur O, Organic & Biomolecular Chemistry, 2015,13, 5716-5733 doi:10.1039/C5OB00498E). The final version is available at http://dx.doi.org/10.1039/C5OB00498

Base-Catalyzed Direct Aldolization of α-Alkyl-α-Hydroxy Trialkyl Phosphonoacetates

Catalytic direct aldol addition of α-hydroxy trialkyl phosphonacetates to aldehydes affords α-hydroxy-β-phosphonyloxy ester products. The fully substituted glycolate enolate intermediate is generated in situ under mild conditions via [1,2]-phosphonate-phosphate rearrangement. High enantioselectivity and dramatic enhancement of reaction diastereocontrol is realized via the application of chiral iminophosphorane catalysts. The phosphate products undergo stereoselective nucleophilic displacement reactions

Stereoselective Reactions with Stabilized Carbocations

Benzylic carbocations, which are easily generated in situ from alcohols or acetates by Brønsted or Lewis acids, undergo selective facial discrimination in diastereoselective reactions (see scheme; FG=functional group). The A values are responsible for the facial selectivity. Catalytic amounts of various Lewis acids can be employed in discriminating one face of the carbocation